MyoD is a bHLH transcription factor which, when expressed in a variety of cell types, converts those cells into muscle. E12 is also a bHLH transcription factor that can bind to similar sequences as MyoD, yet cannot activate muscle specific transcription. Only 3 residues from the MyoD basic region, when placed into E12, converts E12 into a myogenic activator without effecting DNA binding. Similarly, extensive mutagenesis of one of these residues in MyoD (ala-114) leads to a class of "positive control" mutants -- molecules that bind normally, but fail to activate. The primary goal of this proposal is to focus on the nature of this myogenic specificity by determining: (1) whether the positive control mutants bind to target sequences in vivo; (2) what cellular factors "recognize" the basic region "myogenic code"; (3) the 3-d structure of MyoD and MyoD-El2 heterodimers bound to DNA and in solution; (4) the rules for HLH dimerization efficiency; (5) the rules for how the basic region determines a preferred DNA binding site.